Process for the preparation of substituted pregnane-diones



3,007,949 PROCESS FGR TIE PREPARATION F SUBSTITUTED PREGNANE-DIONES Gerard Nomin, Noisy-ie-Sec, Seine, and Daniel Bertin,

Montrouge, Seine, France, assignors to Les Laboratoires Frangais de Chimiotherapie, Paris, France, a corporation of France N0 Drawing. Filed Mar. 23, 1%0, Ser. No. 16,920 Claims priority, application France Mar 27, 1959 5 Ciaims. (Cl. 260--397.45)

The present invention relates to a process for producing 1 1a,17a-dihydroxy-16a-methylpregnane-3,ZO-dione starting with the corresponding 3a-acyloxy-l6u,17u-epoXy-20- ethylene-dioxy-l6fl-methyl-pregnane-ll-one, where acyl represents the acyl radical of an organic carboxylic acid having from one to eight carbon atoms.

In United States patent application Serial No. 2,115, filed January 13, 1960, in the name of one of us, Gerard Nomin, and commonly assigned, there is described a process for the preparation of pregnane-diones of the general formula wherein According to the process described in this application, A -pregnane-3,11,20-trione is condensed with diazomethane. The pyrazoline obtained thereby is subjected to thermolysis to give 16 methyl A pregnene 3,11,20- trione. The 3,20-diketa1 of this latter compound is prepared and reacted with the percarboxylic acid to form the 16,17-epoxide. Treatment of the 3,20-diketal of 1604,17czepoxy-16B-methyl-pregnane 3,11,2O trione so produced with lithium in the presence of an aliphatic amine results in saponification of the epoxide function and simultaneous reduction and steric inversion of the ll-keto group. By acid cleavage of the 16wmethyl-l7a-hydroxy1ated diketal obtained thereby, 11a, 17et-dihydroxy-l6ot-methyl-pregmane-3,20-dione is obtained. This latter compound can be oxidized into 170: hydroxy 16cc methyl pregnanc- 3,11,20-trione.

The present invention has as an object the development of a very economical process for the preparation of this 1 17ct-CllhYdlOXY-l 6a-methyl-pregnane-3,20-dione I, wherein R=\ useful as an intermediate in the preparation of hexadecadrol 16a-methyl-9 ot-fluoro-prednisolone).

Another object of the invention is the obtention of the novel intermediates, 3a,lla,17a-trihydroxy-20ethylene-dioxy 16oz methyl pregnane and 3a,11a,17a-trihydroxy-l6a-methyl-pregnane20-one.

These and other objects of the invention will become more apparent as the description thereof proceeds.

We have found that 11a,l7a-dihydroxyl6a-methylpregnane-3,20-dione can be obtained starting with 3a-acylcry-16a,17a-epoxy-20-ethylenedioxy 16B methyl pregnane-l l-one, Where acyl represents the acyl radical of an nited htates Patent 3,@'Z,%9 Faienized Nov. 7, i961 EQQ organic carboxylic acid having one to eight carbon atoms, by a series of reactions the progression of which is shown in the schematic flow sheet of Table I.

TABLE I O l C D AcO- Ac represents the acylradical of an organic carhoxylic acid havlng one to eight carbon atoms The series of reactions is efiected in the following manner:

A 3a-acyloxy-l6u,l7ot-epoxy 20 ethylenedioxy -methyl-pregnane-ll-one (Ii), Where acyl represents the acyl radical of an organic carboxylic acid having one to eight carbon atoms, is subjected to the action of lithium in the presence of a lower alkylamine such as methylamine, at temperatures from 6 C. to 40 C., preferably at about 20 C., which yields, by simultaneously opening the epoxide ring in the 16,17-position with steric inversion, reducing the ketone function in the ll-position and saponifying the acyloxy function in the 3-position, the trihydroxylated compound, 3oz,l10:,l7ac-it'lhYd1'OXY-2Q- ethylenedioxy-l6a-methyl-pregnane (III) with practically quantitative yields due to the presence of the lower alkylamine such as methylamine. The hydrolysis of the 20-ethylenedioxy function of the triol III in an acid medium leads to 3cr,11a,17a-trihydroxy-16o-methyl-pregnane-20-one (IV). This mono ketone IV is reacted with a selective oxidizing agent, an N-bromoamide or N- bromoimide such as N-bromo-succinimide in an aqueous, water-miscible organic solvent such as acetone at temperatures from about C. to room temperature, in such a way as to convert the hydroxyl group in the 3-position into a keto group. The desired 11a,17a-dihydroxy-16amethyl-pregnane-3,ZO-dione is then recovered. The invention also includes the intermediate products used in the present process for the preparation of llot,17a-dlhydroxy-l6u-methyl-pregnane-3,ZO-dione, namely 3a,lloz, 17u-trihydroxy 20 ethylenedioxy-l6lx-methyl-pregnane and 300,1 1a,17a-trihydroxy-16m-methyl-pregnane-ZO-one.

The 11e,l7a-dihydroxy-16oi-methyl-pregnane 3,20-dione is useful as an intermediate in the preparation of the known hexadecadrol (16u-methyl-9or-fiuoroprednisolone). It can be transformed into 17u,21-dihydroxy-16amethyl-A -pregnene-3,20-dione by dehydration in the 9,11-position and microbiological hydroxylation in the 21-position, particularly by the enzymatic action of Collezozl'ichzrm lindemuthz'anum (ATCC' 12611) as described in US. Patent No. 2,805,978, issued September 10, 1957. In addition, it can be acetyloxylated in the 21-position by known chemical means. The M -pregnene-ZI-Ql is acetylated in the 21-position in accordance with known processes, and then dehydrogenated, for example, by conventional microbiological procedures, to create double bonds in the 1,2 and 4,5-positions, thereby yielding 17a-hydroxy-2l-acetoxy 16a methyl-A -pregnatriene3,20-dione (described by Oliveto et al., J. Am. Chem. Soc. 80, 4431 (1958)), which in turn is converted to hexadecadrol by formation of the fluorohydrin (the 9e-fluoro-11fl-hydroxy derivative).

As a starting material for the process of the invention, 3or-acetoxy-l6oz,17a-epoxy-20-ethylenedioxy-16,8 methylpreguane-ll-one (II, where AcO=acetoxy) is conveniently used. This 3a-acetoxy compound is obtained according to the process described in US. patent application Serial No. 863,110, filed December 31, 1959, now Patent No. 2,945,029, in the name of one of us, Gerard Nomin, and commonly assigned, by reacting 30cacetoxy-l6-methyl-A pregnene-11,20-dione (Oliveto, I. Am. Chem. Soc. 80, 4428 (1958)) with ethylene glycol in an anhydrous acid medium to obtain the 3or-acetoxy- 20ethylenedioxy-16-methyl-A -pregnene-1l-one. The latter compound is treated in an inert organic solvent with a percarboxylic acid such as perphthalic acid and 30aocetoxy-16a,17wepoxy-ZO-ethylenedioxy 16p methylpregnane-11-one is recovered.

Other starting 3a acyloxy-16-methyl-A -pregnenell,20diones can be utilized in the above process to produce other 3a-ZICYlOXY-161x,17cc-GPOXY-ZO-CihYleIledlOXY- 165-methyl-pregnane-1l-ones. These other 3m-acyloxy compounds can be prepared by conventional methods such as saponification and re-esterification or ester interchange from the 3u-acetoxy compound. Any acyl radical derived from an organic carboxylic acid having from one to eight carbon atoms can be used, such as those derived from benzoic acid, acetic acid, propionic acid, cyclohexane carboxylic acid, etc.

While the process of the invention is described utilizing a 3a-acyloxy-16e,17u-epoXy-20-ethylenedioxy-16;?- methyl-pregnane-ll-one (II) as a starting material, any other ZO-ketal can likewise be used in the process as the function of the ketal is to protect the ZO-ketone function from undergoing reaction while reducing the ll-ketone function. The kctal prepared from ethylene glycol is preferred due to its case of preparation.

The following example illustrates the invention without, however, limiting it. The temperatures are indicated in degrees centigrade.

EXAMPLE Preparation of 1104,] 7 a-dihydroxyJ 6 u-methyl-pregnane- 3 ,ZO-dione /H I, R:

(a) 3a,11a,17a.TRIHYDROXY-ZOETHYLENEDIOXY-lfia- METHYL-PREGNANE (III) 0.5 gm. of lithium are introduced, under agitation and in an atmosphere of nitrogen, at 20 C. into a mixture of 2 gm. of 3a-acetoxy-16a,17aepoxy-ZO-ethylenedioxypregnane-ll-one (II), and 60 cc. of methylamine. The steroid II is obtained starting with 3a-acetoxy-16-methyl- A -pregnene-l1,20-dione, by preparing the corresponding ZO-ethylene-ketal and reacting it with perphthalic acid. The reaction mixture is agitated at 20 C. for five hours, then 1 gm. of ammonium chloride is added. The methylamine is distilled off and the residue is taken up in 400 cc. of water. The aqueous mixture is neutralized to a pH of 7 by addition of acetic acid and extracted with ether. The extracts are combined and washed with water, with a solution of sodium bicarbonate, then again with water, dried over sodium sulfate and distilled to dryness. Yield: 1.76 gm. (97% of theory) of the product melting at 235 to 240 C. 3a,1lrx,170c trihydroxy-20-ethylenedioxy 160a methylpregnane (III) obtained thereby is used without any further purification for the following stage of the synthesis. For analysis, the product is recrystallized from isopropyl ether and from methanol. The crystalline compound III has a melting point of 247 to 250 C. and a slow melting point of 240 C. with sublimation. It is very slightly soluble in water and soluble in ether.

Analysis.Calculated: C H O molecular weight: 408.56. C, 70.55%; H, 9.87%; O, 19.58%. Found: C, 70.3%; H, 9.8%; O, 20.3%.

This compound is not described in the literature.

(11) 3a,1 1a,17a-TRIHYDROXY-l Sa-METHYL-PREGNANE- ZO-ONE (IV) 1.75 gm. raw compound III, having a melting point of 235 to 240 C. prepared according to (a) above, are heated to C. under an atmosphere of nitrogen in 17.5 cc. of 80% acetic acid. After an hour and a half of heating, the mixture is poured into a mixture of cc. of water, 25 cc. of caustic soda and 100 gm. of ice. Compound IV precipitates. It is extracted with ether, the extracts are combined and Washed with water, dried and distilled to dryness to recover 1.52 gm. of 3a,lluc,l7oz-trihydroxy-16a-methyl-pregnane-20-one (IV) (98% of theory) melting at 195 to 199 C. By recrystallization from isopropyl ether, a product with a melting point of 210 to 211 C., a slow melting point of 172.5 to C., and a specific rotation [a] =+33.8 (c=1% in ethanol), is obtained with a yield of 84%. Recrystallization from ethyl acetate and acetone does not change the melting point. The novel product IV is very slightly soluble in water; slightly soluble in isopropyl ether, acetone, benzene and chloroform; and soluble in alcohol and ethyl acetate.

Analysis.C H O molecular weight=364.51. Calculated: C, 72.49%; H, 9.96%. Found: C, 72.4%; H, 9.9%.

This compound is not described in the literature.

(a) 1 1 a, 17a-DIHYDROXY-1 6a-METHYDPREGNANE- 3 ,20-DIO NE 0.5 gm. of compound IV prepared according to (b) above is suspended in 10 cc. of an aqueous acetone solution containing 33% Water. After cooling the suspension to +2 C., 0.58 gm. of N-bromo-succinimide is added. The reaction mixture is agitated for one-half hour at +20 C.; the product dissolves and the solution turns orange. After allowing it to stand for an hour and a half at +2 C., 3 drops of a saturated aqueous solution of sodium bisulfite are added until the solution becomes colorless. The acetone is distilled off in vacuo, the residue is taken up with 5 cc. cold water, compound I is separated on a vacuum filter, and the filter cake is Washed with water and dried. Yield: 0.465 gm. (94% of theory) of 1la,l7a-dihydroxy-16a-methyl-pregnane-3,20-dione melting at 192 C. The product is purified by recrystallization from ethyl acetate, yielding 0.370 gm. of a product melting at 198 C., which is identical in all respects to the product described in commonly assigned United States Patent application Serial No. 2,115, filed January 13, 1960.

The above example is non-limiting and it is evident that the temperatures and/or the solvents may be varied and that other equivalent techniques known to those in the art may be used without departing from the spirit of the invention. Thus it is possible to use other 3a-acyloxy derivatives in place of the 3a-acetoxy starting compound; to use other ZO-ketals in place of the ZO-ethylenedioxy starting compound; to use other N-bromoamides and N- bromoimides in place of N-bromo-succinimide; and to use other acids in place of acetic acid for the cleavage of the ketal. These and other expedients known to those skilled in the art may be employed without departing from the spirit of the invention or the scope of the appended claims.

We claim:

1. A process for the preparation of lloc,l70c-dihy droxy-16a-methyl-pregnane-3,ZO-dione which comprises the steps of treating 3a-acyloxy-16a,17u-epoxy-20-ketall6fi-methyl-pregnane-ll-one in a lower alkylamine with lithium at a temperature from 6 C. to C., for a time sufiicient simultaneously to effect an opening of the epoxide ring in the 16,17-position with sten'c inversion, reducing the ketone function and saponifying the acyloxy group, hydrolyzing the 3e,11a,l7e-trihydroxy- 20-ketal-l6nt-methyl-pregnane with an aqueous acid, treating the 311,1let,l7u-trihydroxy-16or-methyl-pregnane-2O- one with an oxidizing agent selected from the group consisting of N-bromoamides and N-bromoimides in an aqueous, water-miscible organic solvent at temperatures from about 0 C. to room temperature for a time sufiicient to oxidize the hydroxyl group in the 3-position and recovering said 11a,17a-dihydroxy-16a-methyl-pregnane-3,20- dione.

2. The process of claim 1 wherein the starting compound is 3ot-acetoxy-16a,17a-epoxy-20-ethylenedioxy-165- methyl-pregnane-l l-one.

3. The process of claim 1 wherein said first treating step is effected in methylamine with lithium at a temperature of about 20 C.

4. The process of claim 1 wherein said hydrolyzing step is eifected with aqueous acetic acid.

5. The process of claim 1 wherein said second treating step is effected with N-bromosuccinimide in acetone.

Fonken et al. Aug. 2, 1955 Nomine July 12, 1960 UNITED STATES PATENT OFFICE CERTIFICATION OF CORRECTION Patent No. 310071949 November 7 1961 Grard Nomin et a1.

- It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, lines 22 to 30 the formula should appear as.

" shown below instead of as, in the patent: 1

R --OH lines 56 to 60, the formula should appear as shown below instead of as in the patent:

II, wherein R:\

column 3, line 56, for "ocetoxy" read acetoxy column 4.

lines 10 to 15 the formula should appear as shown below instead of as in the patent:

line 44, strike out, 'Calculated:" and insert the same after '0 "408.56., l Lne 45 same column 4; column 5 line 12, for "+20'-- C."

read +2 C. a

Signed and sealed this 1st day of May 1962a (SEAL) Attest:

ERNEST W. SWIDER DAVID L. LADD Attesting Officer Commissioner of Patents 

1. A PROCESS FOR THE PREPARATION OF 11A,17A-DIHYDROXY-16A-METHYL-PREGNANE-3,20-DIONE WHICH COMPRISES THE STEPS OF TREATING 3A-ACYLOXY-16A,17A-EPOXY-20-KETAL16B-METHYL-PREGNANE-11-ONE IN A LOWER ALKYLAMINE WITH LITHIUM AT A TEMPERATURE FROM -6*C. TO -40*C., FOR A TIME SUFFICIENT SIMULTANEOUSLY TO EFFECT AN OPENING OF THE EPOXIDE RING IN THE 16,17-POSITION WITH STERIC INVERSION, REDUCING THE KETONE FUNCTION AND SAPONIFYING THE ACYLOXY GROUP, HYDROLYZING THE 3A,11A,17A-TRIHYDROXY20-KETAL-16A-METHYL-PREGNANE WITH AN AQUEOUS ACID, TREATING THE 3A,11A,17A-TRIHYDROXY-16A-METHYL-PREGNANE-20ONE WITH AN OXIDIZING AGENT SELECTED FROM THE GROUP CONSISTING OF N-BROMOAMIDES AND N-BROMOIMIDES IN AN AQUEOUS, WATER-MISCIBLE ORGANIC SOLVENT AT TEMPERATURES FROM ABOUT 0*C. TO ROOM TEMPERATURE FOR A TIME SUFFICIENT TO OXIDIZE THE HYDROXYL GROUP IN THE 3-POSITION AND RECOVERING SAID 11A,17A-DIHYDROXY-16A-METHYL-PREGNANE-3,20DIONE. 